1. Field of the Invention
The present invention relates to new thiol esters of S-substituted 11xcex2-benzaldoxime-estra-4,9-diene-carboxylic acid of the general formula I 
and to their pharmaceutically acceptable salts, to a method for their synthesis and to pharmaceutical preparations containing these compounds.
2. Description of the Related Art
The EP-A-0 648 778 and the EP-A-0 648 779 disclose esters, carboxylate esters and urethanes of 11xcex2-benzaldoxime-estra-4,9-dienes. The compounds described therein have anti-progestational activity.
Anti-progestogens are steroids which, like progesterone and other progestational substances, have a high affinity for the progesterone receptor. However, they are different from these in that they do not lead to the typical physiological effects, which are brought about by the progesterone receptor. Instead, progesterone is displaced from its bonding to the receptor and its activity is inhibited. From the scientific literature, it is known that, aside from the displacement of progesterone from its binding site, malfunctions of the gene-regulatory receptor function play a decisive role here.
(Klein-Hitpass, L., Cato, A. C. B, Henderson, D., Ryffel, U.: Nucleic Acid Res. 19 (1991), 1227-1234; Horwitz, K. B.: Endocrine Rev. 13 (1992) 146); McDonnell D. P.: Trends Endocrinol. Metab. 6 (1995) 133-138).
With respect to the last-mentioned aspect, known antagonists, for example ZK 98299=onapristone (DE-A-35 04 421) and RU 486=mifepristone (EP-A-0 057 115) differ at the molecular level (type I/type II antagonists) and indeed in that in the case of type I antagonists (e.g. onapristone), the hormone receptor complex no longer binds to the hormone-responsible elements or binds in a labile manner, whereas with type II (e.g. Ru 486) this is still the case (Klein-Hitpass et al.). Antigestagens which still allow receptor binding to DNA can have progesterone-like actions, while in the case of disturbance of the DNA binding of the receptor this is not possible.
Modulation of gene-regulatory activity of individual progesterone antagonists can also take place by mechanisms which initially start from the receptor protein. Various studies have demonstrated that the gene-regulatory activity of antagonist-receptor complexes is stimulated by cyclic AMP. In the presence of high concentrations of c-AMP in the tissue, activation of the antagonist-receptor complexes manifests itself; at low concentrations the receptor remains inhibited with respect to gene-regulatory activity. The occurrence of corresponding phenomena is apparently also substance-specific. The production of high c-AMP concentrations (in vitro) leads to partial agonistic action in some antigestagens; in other substances corresponding effects are, however, not caused by c-AMP (Sartorius, C A., Tung, L., Takmoto, G S., Horwitz, K B.: J Biol. Chem 268 (1993) 9262-9266; Sobek, L., Kaufmann, G., Schubert, G., and Oettel, M., 79th Annual Meeting of the Endocrine Society 1997, 3-452, 549).
Differences at the molecular level are also expressed in the pharmacodynamic behavior of progesterone antagonists. This can be demonstrated in the very different pharmacodynamic behavior of substances which are very well characterized in vivo and in vitro, such as onapristone and mifepristone (RU 486) [Elger, W., W., Neff, G., Beier, S., Fxc3xa4hnrich, M., Grundel, M. et al. in Current Concepts in Fertility Regulation and Reproduction, ed. Puri, C. P. and Van Look, P. F. H. (1994) 303-328.
Progesterone plays a crucial role in the control of the organ systems involved in reproductive processes. This applies to the morphological metaplastic processes in the genital tract and in the mammary gland, the regulation of hormones of the anterior pituitary lobe and of the genital organs or the inhibition and activation of parturition. These functions react with different sensitivity to progesterone. Processes which take place at very low progesterone levels deserve particular consideration with respect to the pharmacology of the antigestagens. xe2x80x9cPurexe2x80x9d progesterone antagonists of type I can bring about effects which can be achieved with no [sic] dose using partial agonistic antagonists. This generally ought to be the case when the threshold for the respective effect is low, that is below the partial agonistic activity of a progesterone antagonist. Conversely, there is the possibility that under the influence of progesterone antagonists of type II, effects are observed which are caused not by the inhibition, but by the activation of the progesterone receptor. At an identical dose of this antagonist, the functions of progesterone are inhabited which proceed at high tissue concentrations.
An example of the first-mentioned case is the prostaglandin secretion of the uterus in the guinea pig during its menstrual cycle. This is stimulated toward the end of the cycle by very low progesterone levels. Only pure progesterone antagonists of type I are able to inhibit the progesterone secretion of the uterus in guinea pigs to such an extent that the reformation of the corpus luteum is completely inhibited (Elger, W., Neef, G., Beier, S., Fxc3xa4hnrich, M., Grundel, M., et al. in Current Concepts in fertility Regulation and Reproduction, ed. Puri, C. P. and Van Look, P. F. H. 1994 303-328). Partial agonistic substances inhibits this process little or not at all.
In the human, the progesterone antagonist RU 486 has various effects on reproductive functions which are relevant to use in therapy. This substance inhibits the action of progesterone to such an extent that when used during pregnancy the induction of an abortion occurs. This abortion- or labor-inducing property is considerably increased by simultaneous or sequential treatment with a prostaglandin (Van Look, P. F. A.; Bygdeman, M.: Oxf. Rev. Reprod. Biol. 11 (1989), 1-60; Elger, W., Neef, G., Beier, S., Fxc3xa4hnrich, M., Grundel, M. et al. In Current Concepts in Fertility Regulation and Reproduction, ed. Puri, C. P. and Van Look, P. F. H. 1994 303-328). Corresponding effects can be adequately explained on the basis of the pregnancy-regulating function of progesterone in pregnancy.
In addition, RU 486 and other antigestagens have effects in which the mechanism of the withdrawal of progesterone is not so clearly confirmed. This relates primarily to effects in the menstrual cycle in phases in which the progesterone levels in the blood are very low. Here, two phenomena are to be mentioned in particular, the inhibition of ovulation (Croxatto, H. B., Salvatierra; A. M.; Croxatto, H. D.; Fuentealba, A.: Hum. Reprod. 8 (1993), 201-207) and the inhibition of the estrogen-induced proliferation of the genital epithelia, in particular those of the endometrium (Wolf, J. P., Hsiu, J. G., Anderson, T. L., Ulmann, A., Baulieeu, E. E. and Hodgen, G. D.: Fertility and Sterility 52 (1989) 1055-1060). Corresponding effects are of central importance for the use of the antigestagens, in particular for antiovulatory strategies in fertility control, the reversible induction of amenorrhea, for example in the therapy of endometriosis and for the suppression of undesired estrogenic effects in the endometrium in the course of a substitution therapy with estrogens in the menopause. The coupling of the abortive and labor-inducing action with the progesterone-agonistic and in particular the antiovulatory and proliferation-inhibiting properties is of advantage for the therapeutic use of type I antagonists such as RU 486.
The object of the present invention is therefore to make available compounds which overcome the disadvantages outlined above.
The object is achieved by making available compounds of the general formula I 
according to Claim 1 and their pharmaceutically acceptable salts and also a process for their preparation. Pharmnaceutical compositions are further made available which contain a compound of the general formula I or its pharmaceutically acceptable salt.
The present invention thus relates to S-substituted 11xcex2-benzaldoxime estra-4,9-dienecarbonic acid thioesters of the general formula I, 
in which
R1 is an alkyl radical having 1-10 carbon atoms, an aryl radical having 6-10 carbon atoms or an alkylaryl or arylalkyl radical each having 7-10 carbon atoms,
R2 is an alkyl radical having 1-3 carbon atoms or a hydrogen atom,
R3 is a hydroxyl group, an O-alkyl group having 1-10 carbon atoms, an O-aryl group having 6-10 carbon atoms, an O-aralkyl, or O-alkylaryl group each having 7-10 carbon atoms, a radical xe2x80x94OCOR5, xe2x80x94OCONHR5 or xe2x80x94OCOOR5,
where
R5 is a hydrogen atom, an alkyl group having 1-10 carbon atoms, an aryl group having 6-10 carbon atoms, an aralkyl or alkylaryl group each having 7-10 carbon atoms,
R4 is a hydrogen atom, an alkyl group having 1-10 carbon atoms, an aryl group having 6-10 carbon atoms, an aralkyl or alkylaryl radical each having 7-10 carbon atoms,
a radical xe2x80x94(CH2)nCH2Y,
where
n=0, 1 or 2,
Y is a fluorine, chlorine, bromine or iodine atom, a cyano, amino, azido or thiocyano group, or is a radical xe2x80x94OR6, xe2x80x94SR6, xe2x80x94(CO)SR6 or xe2x80x94(CO)OR6, where
R6 is a hydrogen atom, an alkyl group having 1-10 carbon atoms, an aryl group having 6-10 carbon atoms, an aralkyl or alkylaryl radical each having 7-10 carbon atoms,
or is a radical xe2x80x94COR5, where R5 has the meaning indicated above,
is a radical xe2x80x94OR5 or xe2x80x94OCOR5, where R5 has the meaning indicated above,
is a radical xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CH(CH2)pxe2x80x94R6,
where
m=0, 1, 2 or 3,
p=0, 1 or 2 and
R6 has the meaning indicated above or is a radical xe2x80x94OR5 or xe2x80x94OCOR5, where R5 has the meaning indicated above,
is a radical xe2x80x94(CH2)oCxe2x89xa1CR7,
where
o=0, 1 or 2 and
R7 is a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, an alkyl group having 1-10 carbon atoms, an aryl group having 6-10 carbon atoms, an aralkyl or alkylaryl radical each having 7-10 carbon atoms or is a radical xe2x80x94OR5, where R5 has the meaning indicated above,
or is a radical xe2x80x94OCOR5, where R5 has the meaning indicated above,
or is a radical xe2x80x94CH2OR5, where R5 has the meaning indicated above,
or is a radical xe2x80x94Cxe2x89xa1CCH2OH,
or R3 and R4 together form an arbitrarily substituted five- or six-membered ring having at least one carbon atom and 0-4 heteroatoms from the group consisting of oxygen, sulfur, selenium, tellurium, nitrogen, phosphorus, silicon or germanium.
Preferred compounds are those where R1 is an alkyl radical having 1-6 carbon atoms. Preferred compounds are also those in which R2 is a methyl or ethyl group. It is furthermore preferred that R3 is a hydroxyl group or an O-alkyl group having 1-6 carbon atoms.
Particularly preferred compounds are those in which R4 is a radical xe2x80x94OR5 or xe2x80x94OCOR5, where R5 is an alkyl radical having 1-6 carbon atoms.
It is furthermore preferred according to the invention that R4 is a radical xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CH(CH2)pxe2x80x94R6, where
m=1 and p=1 and
R6 is an alkyl radical having 1-6 carbon atoms or a group xe2x80x94OR5 or xe2x80x94OCOR5, where
R5 is a hydrogen atom or an alkyl group having 1-6 carbon atoms.
Preferred compounds according to the invention are moreover those in which R4 is a radical xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CH(CH2)pxe2x80x94R6, where
m=0 and p=1 and
R6 is a group xe2x80x94OR5 or xe2x80x94OCOR5, where
R5 is a hydrogen atom or an alkyl group having 1-6 carbon atoms.
Particularly preferred compounds are also those in which R4 is a radical xe2x80x94(CH2)oCHxe2x89xa1CR7, where
o=1 and
R7 is an alkyl group having 1-6 carbon atoms or a radical xe2x80x94OCOR5, or is a radical xe2x80x94CH2OR5, where
R5 is an alkyl radical having 1-6 carbon atoms or a hydrogen atom.
Compounds according to the invention are moreover preferred in which R4 is a radical xe2x80x94(CH2)nCH2Y, where
n=0 or 1,
Y is an F, Cl, Br or iodine atom, a cyano, amino, azido or thiocyano group,
or is a radical xe2x80x94OR6 or xe2x80x94SR6, xe2x80x94(CO)SR6 or xe2x80x94(CO)OR6, where
R6 is a hydrogen atom or an alkyl group having 1-10 carbon atoms.
Preferred compounds according to the invention are furthermore characterized in that R3 and R4 together form an arbitrarily substituted five- or six-membered ring having at least one carbon atom and 0-4 heteroatoms, where
the heteroatoms originate from the group consisting of oxygen, sulfur and nitrogen.
Particularly preferred compounds here are those where a five-membered ring is formed which contains 1 or 2 heteroatoms.
Very particularly preferred compounds according to the invention are those where the ring is a heterocycle from the group consisting of oxazolidinone, oxazolinone, thiazolidinone, thiazolinone, imidazolidinone, imidazolinone, 1,3-dioxolanone, 1,3-dioxolenone, 1,3-oxathiolanone, 1,3-oxathiolenone, pyrrolidinone, pyrrolinone, oxazolidinethione, oxazolinethione, thiazolidinethione, thiazolinethione, imidazolidinethione, imidazolinethione, dioxolanethione, pyrrolidinethione and pyrrolinethione.
Even more preferred here are compounds where the five-membered ring is an oxazolidin-2-one or an oxazolidine-2-thione.
Those most preferred are:
4-[17xcex2-methoxy-17xcex1-(methoxymethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(methylthio)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-(methoxymethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(methylthio)carbonyl]oxime,
4-[17xcex2-methoxy-17xcex1-(methoxymethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(ethylthio)carbonyl]oxime,
4-[17xcex2-methoxy-17xcex1-(methoxymethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(Z)[O-(ethylthio)carbonyl]oxime,
4-[17xcex2-methoxy-17xcex1-(ethoxymethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(ethylthio)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-(methoxymethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(n-propylthio)-carbonyl]oxime,
4-[17xcex2-methoxy-17xcex1-(n-propoxymethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(methylthio)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-(i-propoxymethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(ethylthio)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-(methoxymethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(ethylthio)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-Z-(3-hydroxypropenyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(methylthio)-carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-E-(3-hydroxypropenyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(methylthio)-carbonyl]oxime,
4-[17xcex2-methoxy-17xcex1-(3-hydroxy-1-propinyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(ethylthio)-carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-(azidomethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(methylthio)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-(chloromethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(ethylthio)carbonyl]oxime,
4-[17xcex2-ethoxy-17xcex1-(chloromethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(methylthio)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-(cyanomethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(ethylthio)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-(ethylthiomethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(ethylthio)carbonyl]-oxime,
4-[17xcex2-hydroxy-17xcex1-(ethylthiomethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(methylthio)-carbonyl]oxime,
4-[17xcex2-ethoxy-17xcex1-(methylthiomethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(ethylthio)carbonyl]-oxime,
4-[17xcex2-hydroxy-17xcex1-[(ethylthiocarbonyl]methyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(ethylthio)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-(aminomethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde 1-(E)[O-(ethylthio)carbonyl]oxime and
(17R)-4-{3-oxoestra-4,9-dien-17-spiro-5xe2x80x2-oxazolidin-2xe2x80x2-on-11xcex2-yl}benzaldehyde 1-(E)-[O-(ethylthio)-carbonyl]oxime.
The present invention further relates to a process for the preparation of the compounds of the general formula 1 [sic] according to the invention.
The process according to the invention for the preparation of S-substituted 11xcex2-benzaldoxime estra-4,9-dien carbonic acid thioesters of the general formula I, 
in which R2, R3 and R4 have the meaning indicated above, is characterized in that, in a manner known per se, a compound of the general formula II, 
in which R2, R3 and R4 have the same meaning as R2, R3 and R4 in the formula I, is reacted by treatment with a formic acid derivative of the formula III
Nuc-(CO)xe2x80x94SR1xe2x80x83xe2x80x83(III)
in which
R1 has the abovementioned meaning and Nuc is a nucleophile,
in a solvent and converted into a compound of the general formula I.
A process is preferred here where the solvent employed is a tertiary amine and the reaction is carried out at a temperature between 20xc2x0 C. and 80xc2x0 C.
A process is particularly preferred in which the reaction is carried out using chloroformic avid thioesters in pyridine or triethylamine at a temperature between 20xc2x0 C. and 40xc2x0 C.
The starting compounds of the general formula II are prepared, if not stated otherwise, by the procedures of the specifications EP-A-0 648 778 or EP-A-0 648 779.
The pharmaceutically acceptable salt is prepared into the I [sic] known manner. Customary physiologically tolerable inorganic and organic acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other utilizable acids are described, for example, in Fortschritte der Arzneintmittelforschung, Vol. 10, pages 224-225, Birkhxc3xa4user Verlag, Basle and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, Vol. 66, pages 1-5 (1977).
As a rule, the acid addition salts are obtained in a manner known per se by mixing the free base or its solutions with the corresponding acid or its solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, n-propanol or isopropanol or a lower ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane. For better crystal deposition, mixtures of the solvents mentioned can also be used. Physiologically tolerable aqueous solutions of acid addition salts of the compound of the formula I can moreover be prepared in an aqueous acid solution.
The acid addition salts of the compounds of the general formula I can be converted into the free base in a manner known per se, e.g. using alkalis or ion exchangers. Further salts can be obtained from the free base by reaction with inorganic or organic acids, in particular those which are suitable for the formation of therapeutically utilizable salts. These or alternatively other salts of the novel compound, such as, for example, the picrate, can also be used for the purification of the free base by converting the free base into a salt, separating this off and in turn liberating the base from the salt.
A further subject of the present invention is pharmaceutical compositions characterized in that they contain at least one compound of the general formula I.
The present invention also relates to medicaments for oral, rectal, subcutaneous, intravenous or intramuscular administration, which together with the customary vehicles and diluents contain at least one compound of the general formula I as active compound.
The medicaments of the invention are prepared in a suitable dose and in a manner known per se using the customary solid or liquid vehicles and/or diluents and the customarily used pharmaceutical excipients according to the desired type of administration. The preferred preparations exist in an administration form which is suitable for oral administration. Such administration forms are, for example, tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, solutions or suspensions or depot forms.
Of course, parenteral preparations such as injection solutions are also suitable. Suppositories, for example, may furthermore also be mentioned as preparations.
Suitable tablets can be obtained, for example, by mixing the active compound with known excipients, for example dextrose, sugar, sorbitol, mannitol, polyvinyl-pyrrolidone, disintegrants such as cornstarch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents which can achieve a depot effect, such as carboxylpolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consists of a number of layers.
Accordingly, sugar-coated tablets can be produced by coating cores prepared analogously to the tablets with agents customarily used in sugar-coated tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The sugar-coated shells can in this case also consist of a number of layers, where, for example, the excipients mentioned above in the case of the tablets can be used.
The solutions or suspensions containing the active compound according to the invention can be treated to improve the flavor with substances such as saccharin, cyclamate or sugar and/or with aromatic substances, such as vanillin or orange extract. They can furthermore be mixed with suspension aids such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoic acid.
Capsules can be prepared by mixing the medicament with carriers such as lactose or sorbitol, which are then incorporated into the capsules.
Suppositories are prepared, for example, by mixing the active compound with suitable excipients such as neutral fats or polyethylene glycols or its [sic] derivatives.
The compounds of the general formula I according to the invention are bound to the progesterone receptor (cf. Table 1) and in comparison to RU 486 have a markedly reduced antiglucocorticoidal action, demonstrated by the decreased glucocorticoid receptor binding in vitro (cf. Table 1).
J 867=11xcex2-[4-(hydroximinomethyl)phenyl]-17xcex2-methoxy-17xcex1-methoxymethyl-estra-4,9-dien-3-one (EP-A-0 648 778 and EP-A-0 648 779)
It was surprisingly found that substances according to the invention which had a very high affinity for the progesterone receptor (see Table 1) were not able or only able at very high doses to interfere with early pregnancy in rats. The substances according to the invention (such as, for example, J 1042) proved incapable even at very high doses of interfering with the pregnancy of guinea pigs (see Table 3).
In spite of high receptor affinity, the compounds according to the invention do not result in any inhibition of luteolysis. It is surprising, then, that the compounds of the formula I have antiovulatory and progesterone-analogous activity in the guinea pig. Other than with Onapristone, which induces proliferation and keratinization of the vaginal epithelium in the guinea pig in cycle in spite of high progesterone levels, among the compounds according to the invention (in spite of low progesterone levels in the blood) a complete inhibition of the proliferation of this epithelium and mucification is seen as an expression of progesterone dominance. In this structure, the effect of the substances according to the invention corresponds to that of additionally tested gestagens (progesterone or levonorgestrel).
With respect to other parameters in the guinea pig, the compounds or the formula I according to the invention can be delimited both against xe2x80x9cpurexe2x80x9d antagonists of type I (Onapristone) and against agonists (progesterone). Onapristone leads to very low prostaglandin levels in the blood, progesterone and levonorgestrel, on the other hand, to an increased and prolonged uterine secretion of PGF2xcex1, reflected by raised prostaglandin F metabolite levels (PGMF [sic] levels) in the blood. PGFM is the long-lived main metabolite of the PGF2xcex1 formed by the endometrium, The compounds according to the invention lead to lowered PGFM levels in comparison to control animals in cycle in the luteolysis phase and in comparison to animals treated with gestagen. The PGFM levels are not as low, however, as in animals treated with onapristone.
In rabbits, the substances according to the invention have transformatory activity in the McPhail test and, surprisingly, antitransformatory activity in the same test in combination with progesterone.
Experimental investigations on animals show that the progesterone antagonists according to the invention have such strong partial agonistic actions on the progesterone receptor that abortive effects no longer manifest themselves. Surprisingly, therapy-relevant properties such as, for example, the inhibition of uterine prostaglandin secretion, the inhibition of proliferative processes in tissues of the genital tract and antiovulatory properties, however, are furthermore found.
For the type of active compound described here, the designation mesoprogestinxe2x80x9d is proposed, as the designation antigestagen as defined also implies abortive properties which cannot be demonstrated with the compounds according to the invention in animal experiments.
The compounds according to the invention are high-affinity, highly selective modulators of the steroid receptors. In particular, they are agonists or antagonists of the progesterone and androgen receptors.
A further subject of the present invention is therefore the use of the compounds of the general formula I according to the invention for the treatment of endometriosis, uterus myomatosus, dysmenorrhea and premenstrual syndrome, for the induction of reversible amenorrhea without estrogen deficit and for menopausal substitution therapy (Hormone Replacement Therapy HRT) if appropriate in combination with estrogens. The use for the production of contraceptives is also according to the invention.
The compounds of the general formula I according to the invention are also utilizable, according to the invention, in the following indications, such as dysfunctional uterine hemorrhages, herorrhagia, fertility control and fertility modulation, myoma, leiomyoma, osteoporosis, acne, tumors such as breast tumors, endometrial tumors, ovarian tumors, endometriosis, prostate hyperplasia, prostate tumors, hormone-related alopecia and androgenic conditions and defunctionalization symptoms.